INVIVO INHIBITION OF GLUCOCORTICOID-INDUCIBLE GENE-EXPRESSION BY DIMETHYLNITROSAMINE IN RAT-LIVER

Sprague-Dawley rats were pretreated with a single i.p. injection of ei ther 2.25 mL/kg of phosphate-buffered saline (PBS) or 22.5 mg/kg of di methylnitrosamine (DMN) followed 2 hr later by a single i.p. injection of either 1.35 mg/kg of dexamethasone (DEX) or the vehicle, a 50% eth anol solution, both delivered in a volume of 3 mL/kg. RNA levels of th e hormone-inducible. specialized liver function genes, tyrosine aminot ransferase (TAT) and glutamine synthetase (GS), were monitored 4, 5, 6 , 7, 8, and 10 hr after the DEX injection. Maximal induction of both t he TAT (26-fold) and GS (6-fold) RNAs occurred 6 hr after DEX administ ration in PBS-pretreated animals. Pretreatment with DMN caused at leas t a 42% inhibition of DEX-induced RNA accumulation at every time point examined, with greater than 90% inhibition occurring when the genes w ere maximally induced at 6 hr. This inhibition was not due to any alte rations of the glucocorticoid receptors as DMN had no effect on the bi nding affinity or amounts of glucocorticoid receptors present in rat h epatic cytosols. These results suggest that chemical carcinogens such as DMN may affect normal gene function in vivo by inhibiting the cellu lar response to hormone receptors mediating differentiation-associated , specialized cell functions.